Identification of dual-targeting PROTACs for ataxia telangiectasia and RAD3-related and aurora kinase A as chemo-sensitizers for leukemia cells
Abstract
The ataxia telangiectasia and RAD3-related (ATR) kinase is a central regulator of DNA damage responses. Its pharmacological degradation by proteolysis-targeting chimeras (PROTACs) represents a promising strategy to sensitize cancer cells to DNA-damaging chemotherapy. It is currently unknown if ATR PROTACs can be pharmacologically designed to target a second cancer-relevant kinase. In this study, we report the design, synthesis, and biological evaluation of novel cereblon (CRBN)-based PROTACs for ATR. Structure-guided design and chemical synthesis enabled the development of a focused library of degraders based on selective ATR inhibitors and optimized CRBN ligands. Among the synthesized compounds, Abd141 turns out as the most promising degrader, showing potent ATR degradation in human leukemia cells, without affecting ATM, WEE1 or DNA-PKcs. Consistently, the developed PROTACs prove activity in an in vitro ATR/ATRIP binding assay. Abd141 exhibits high chemical, microsomal, and plasma stability, and no cytotoxicity in non-cancerous HEK293 cells. Proteomic studies and immunoblot experiments identify aurora kinase A (AURKA) as additional target of CRBN-induced proteasomal degradation by Abd141. Dose-degradation studies of Abd141 in the MOLT-4 cell line yielded a DC 50 of 97.7 nM for ATR and 6.7 nM for AURKA. These findings disclose Abd141 as effective dual ATR/AURKA degrader and innovative chemo-sensitizer that encourages preclinical development.
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BibTeX
@article{alfayomy2026identification,
title = {{Identification of dual-targeting PROTACs for ataxia telangiectasia and RAD3-related and aurora kinase A as chemo-sensitizers for leukemia cells}},
author = {Abdallah M Alfayomy and Sarah Neuroth and Anne-Christin Sarnow and Lukas Handke and Dina Robaa and Frank Erdmann and Christophe Decroos and Matthias Schmidt and Christophe Romier and Mike Schutkowski and Oliver H Krämer and Wolfgang Sippl},
journal = {European Journal of Medicinal Chemistry},
year = {2026},
month = sep,
doi = {10.1016/j.ejmech.2026.119125},
url = {https://hal.science/hal-05759967v1},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Identification of dual-targeting PROTACs for ataxia telangiectasia and RAD3-related and aurora kinase A as chemo-sensitizers for leukemia cells
AU - Abdallah M Alfayomy
AU - Sarah Neuroth
AU - Anne-Christin Sarnow
AU - Lukas Handke
AU - Dina Robaa
AU - Frank Erdmann
AU - Christophe Decroos
AU - Matthias Schmidt
AU - Christophe Romier
AU - Mike Schutkowski
AU - Oliver H Krämer
AU - Wolfgang Sippl
PY - 2026
DA - 2026/09/23
JO - European Journal of Medicinal Chemistry
DO - 10.1016/j.ejmech.2026.119125
UR - https://hal.science/hal-05759967v1
AB - The ataxia telangiectasia and RAD3-related (ATR) kinase is a central regulator of DNA damage responses. Its pharmacological degradation by proteolysis-targeting chimeras (PROTACs) represents a promising strategy to sensitize cancer cells to DNA-damaging chemotherapy. It is currently unknown if ATR PROTACs can be pharmacologically designed to target a second cancer-relevant kinase. In this study, we report the design, synthesis, and biological evaluation of novel cereblon (CRBN)-based PROTACs for ATR. Structure-guided design and chemical synthesis enabled the development of a focused library of degraders based on selective ATR inhibitors and optimized CRBN ligands. Among the synthesized compounds, Abd141 turns out as the most promising degrader, showing potent ATR degradation in human leukemia cells, without affecting ATM, WEE1 or DNA-PKcs. Consistently, the developed PROTACs prove activity in an in vitro ATR/ATRIP binding assay. Abd141 exhibits high chemical, microsomal, and plasma stability, and no cytotoxicity in non-cancerous HEK293 cells. Proteomic studies and immunoblot experiments identify aurora kinase A (AURKA) as additional target of CRBN-induced proteasomal degradation by Abd141. Dose-degradation studies of Abd141 in the MOLT-4 cell line yielded a DC 50 of 97.7 nM for ATR and 6.7 nM for AURKA. These findings disclose Abd141 as effective dual ATR/AURKA degrader and innovative chemo-sensitizer that encourages preclinical development.
SN - 0223-5234
SN - 1768-3254
ER -